B cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia among older adults in Western countries and is a significant cause of morbidity and mortality in the older adult population. We believe the B cell receptor (BCR) plays a crucial role in dictating the behavior of the malignant clone in B-CLL and in turn dictates clinical behavior of B-CLL. Our data and that obtained by others provide compelling evidence that the use of specific immunoglobulin heavy chain variable region (IGHV) genes in CLL is non-random and the IGH complementarity determining region 3 (CDR3) is remarkably homologous in certain CLL patients. In addition, the somatic hypermutation (SHM) status of the IGHV gene in the leukemic cell BCR is now a validated and powerful prognostic factor. Regardless of SHM status, all CLL B cells more closely resemble antigen experienced memory rather than naive B cells and some CLL B cells display a molecular phenotype which is similar to BCR-stimulated normal B cells. These observations collectively support the hypothesis that antigenic stimulation influences the development and/or course of B-CLL. Several broad questions concerning the biological role of the BCR in this disease remain unanswered. First, does the BCR continue to play an ongoing role in the biology of B-CLL, and if so, is this uniformly displayed by all patient leukemic B cells? Two, do CLL B cells expressing stereotyped BCRs recognize similar antigens, and if so, does this feature permit insight into the etiology of this disease and can this information be used to devise timely novel therapeutic interventions? Third, what is the relationship between molecular features of the BCR and clinical outcome? We are uniquely positioned to answer these questions because of our exceptional access to primary CLL B cells and an extensive cell bank of over 3000 cryopreserved vials of high quality cells collected as a result of our ongoing efforts to determine the IGHV molecular features of B-CLL patients, now numbering over 1000 patients. In addition, these data are integrated into a clinical data base which features invaluable long term clinical outcome data on each patient as well as expression levels of other biologically relevant molecules with prognostic significance and cytogenetic (FISH) data characterizing the most common CLL-associated genetic abnormalities. Thus, to answer these questions and test our unifying hypothesis that the BCR is functional and plays a critical role in the biology of malignant B cells in B-CLL and clinical outcome of this disease, we propose a comprehensive experimental strategy that will: i) systematically link BCR mediated signaling competencies with molecular BCR features that are critical for in vivo leukemic B cell survival, growth, and accumulation over time;ii) investigate BCR antigen recognition and identify shared epitopes recognized by CLL B cells expressing canonical receptors;and iii) probe the relevance of the BCR to the leukemic B cell process in CLL by correlating various IGHV molecular features with patient clinical outcome and other prognostic factors via our access to an invaluable clinical and research database. PUBLIC HEALTH RELEVANCE: B cell chronic lymphocytic leukemia is a very common leukemia in this country and is currently incurable. Because at least 70 percent of all patients will ultimately require treatment in order to have an enhanced quality of life, avoidance of complications of the disease, and increased survival, we are committed to better understanding the underlying mechanisms that contribute to leukemic cell growth and survival in the patients. This proposal will take a comprehensive approach to define the role of the leukemic B cell antigen receptor in determining the behavior of the malignant B cells and how this in turn dictates patient clinical outcome. Through these studies, we aim to add novel insight into the etiology of this disease and are optimistic that this information can be used to devise timely novel therapeutic interventions.